The present invention relates to a pharmaceutical composition comprising specific compounds which may be obtained from Leontopodium alpinum Cass. (Edelweiss), or structurally related compounds. A preferred compound is leoligin (=(2S,3R,4R)-4-(3,4-dimethoxybenzyl)-2-(3,4-dimethoxyphenyl)tetrahydrofuran-3-yl]methyl (2Z)-2-methylbut-2-enoat]). Corresponding means and methods in respect of medical uses of the compounds are described. The present invention also provides a medical device comprising, containing or having been contacted with the compound. The compounds provided herein may particularly be used in the treatment of hyperplastic diseases, in particular intimal hyperplasia, e.g. stenosis, restenosis, atherosclerosis and the like. Also envisaged herein is the use of these compounds in the treatment of proliferative diseases, such as leukaemia, prostate cancer and lung cancer.
Coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) are the two invasive options to treat coronary artery disease (CAD), being one of the leading causes of morbidity and mortality worldwide; see WHO, Cardiovascular diseases, Internet Communication (2007); see also www.who.int/cardiovascular_diseases/en/. The success of both therapeutic approaches is however often limited by restenosis and graft failure which are considered as hyperplastic diseases/disorders. With respect to graft patency rates after CABG the vessels of choice are clearly the internal mammary arteries; see Tatoulis, Ann Thorac Surg, 77(1), 93-101 (2004). However due to limitations in availability saphenous vein grafts are more frequently used in CABG than arterial grafts (e.g. in 2004 at the Innsbruck Medical University 51% of bypass grafts were saphenous veins; see Schachner, European Surgery 39(2), 72-5 (2007). In past years clinical optimization, like graft handling (e.g. “no touch techniques”) and lipid lowering therapy has impressively increased the patency rates of saphenous vein conduits and is currently approximately at 60% 10 years after CABG (Schachner (2007) loc. cit; Lau, Semin Vasc Med 4(2), 153-9 (2004); Tsui, Eur J Vasc Endovasc Surg 23(3), 202-8 (2002). Still, the major reasons for a loss of patency at earlier time points are thromboses, neointima formation, and intimal hyperplasia, (10-20% loss of patency after the first year), and graft atherosclerosis later after CABG (Lau (2004), loc. cit.; Hozumi, Heart 76(4), 317-20 (1996); Marin, J Vasc Surg 18(3):407-14 (1993). Thus, graft disease still significantly limits the durability of venous bypasses.
Generally, the causative factors and the pathophysiological processes that underlie vein graft disease are not well understood. It is thought that vein graft disease is a result of a variety of events initiated by vascular damage that does occur due to surgical handling, ischemia, and arterialisation (blood pressure, blood flow) of grafts. This initial damage is though to provoke adaptive repair processes in the vessel wall, like tissue remodelling (positive and negative) and intimal hyperplasia; see Lau (2004), loc. cit., Hozumi (1996), loc. cit., Marin (1993), loc. cit; Lau, Circulation 4, 114(1 Suppl):1435-1440 (2006). On one hand this response is vital for the adaptation of the graft to the arterial environment, but an excessive response is thought to give raise to graft disease that ultimately results in graft failure.
Despite a complex array of intra and inter cellular signalling events in the development of graft disease after CABG and/or PCI the core elements on the histological level are endothelial damage (denudation) and smooth muscle cell (SMC) proliferation and infiltration of the intima. Pro-inflammatory signalling due to tissue damage and cellular necrosis but also as an element of adaptive tissue remodelling is another highly relevant factor; see Mitra, Immunol Cell Biol 84(2), 115-24 (2006). Although, the excellent concept of using drug eluting stents/matrices instead of purely mechanical devices will most likely prevail in PCI- and CABG-based prevention of restenosis and graft failure, at the moment there is a significant lack of functional drugs, screened or designed precisely for these applications. Currently used drugs are mainly chemotherapeutic agents developed for cancer or immunosuppressive therapy, which may be too aggressive or unspecific for the treatment of restenosis and graft disease, since also endothelial healing—important for the prevention of thromboses—is impaired by these drugs.
Lignans are considered as potential candidate molecules which may be used in the treatment of diseases/disorders associated with the cardiovascular system and will be discussed herein below in more detail. However, only a limited number of publications have reported on the impact of lignans on the cardiovascular system in general, and only a few different lignans have been tested so far. It is of note that a treatment of hyperplastic diseases/disorders with lignans has not been described in the art. The existing data rather suggest that lignans are cardiovascular protective agents with lipid lowering, anti-oxidative, anti-hypertensive, anti-thrombotic, and anti-inflammatory activities.
A large number of lignan-based cancer therapy studies (in vitro and in vivo) showed profound cytotoxicity and cell death induction by these compounds, see Kim Planta Med, 68(3), 271-4 (2002) and Lin J Cell Biochem 84(3), 532-44 (2002). The use of cytotoxic compounds in the treatment of a hyperplastic disease/disorder, and in particular vein graft disease, is generally considered as detrimental since also healthy cells, such as EC cells can be damaged. Hence, the use of cytotoxic lignans known in the art should be avoided in the treatment of these diseases. Therefore, there is still a demand for compounds which may be used in the treatment of hyperplastic diseases/disorders and which avoid the disadvantages of compounds known in the art.